STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY

在2016财年完成并报告了研究4-甲基环己烷甲醇（MCHM）诱导皮肤致敏的潜力的研究。发现皮肤暴露于纯MCHM在浓度高于20%时在应用部位产生皮肤刺激，在100%浓度时产生明显毒性，但不诱导致敏。用≥75%粗MCHM处理的小鼠也显示出皮肤刺激的证据，尽管与纯MCHM相比较弱。在用100%粗制MCHM处理的小鼠中也有明显毒性的证据，尽管严重程度低于纯MCHM。在≥ 5%的浓度下，皮肤应用粗制MCHM导致引流淋巴结中淋巴细胞增殖增加。与溶剂对照组相比，接受≥20%粗品MCHM处理的小鼠的刺激指数（SI）（致敏性指标）显著增加。这些结果表明，粗品MCHM在无刺激性的暴露浓度下有可能引起皮肤致敏。PAC混合物评估计划（PAC-MAP）提供了一个框架，用于评估单个多环芳香族化合物（PAC），定义的PAC混合物和复杂的PAC含有环境样品的广度，使用体外/短期体内测试电池，包括广泛的端点。某些PAC与广泛的毒性（致癌性、免疫毒性、生殖和发育毒性、神经毒性）和一系列复杂的作用机制相关。特别是，许多PAC与体液免疫功能抑制有关，免疫毒性已被确定为估计PAC致癌潜力的信息参数。作为预测混合效应的潜在测试组合的一部分，我们检查了单个PAC调节抗原特异性抗体应答和影响骨髓细胞学的潜力。 已完成阳性对照苯并（a）芘和效力较低的PAC菲的剂量反应研究，并收到了两项研究的报告草案。另外三种化合物（芘、二苯并噻吩和苊醌）的实验室方案已获得批准，活体研究预计将在2017财年第一季度完成。 在整个发育期和成年早期暴露于地下水污染物环丁砜的成年小鼠和大鼠中完成了对口服暴露于地下水污染物环丁砜的潜在免疫毒性评估的活体部分。评估暴露于饮用水污染偏钒酸钠后免疫功能的筛查研究也已完成。 这些研究的报告草案预计将在2017财年第1季度发布。 在B6 C3 F1/N小鼠和HSD大鼠吸入暴露于多壁碳纳米管30天后进行的两组免疫毒性研究已经完成，第三项研究的活体工作正在进行中，暴露持续时间为90天。

Studies to investigate the potential for 4-Methylcyclohexanemethanol (MCHM) to induce dermal sensitization were completed and reported in FY16. Dermal exposure to pure MCHM was found to produce irritation of the skin at the application site at concentrations above 20% and overt toxicity at the 100% concentration, but did not induce sensitization. Mice treated with ≥75% crude MCHM also showed evidence of dermal irritation, although weaker when compared to pure MCHM. There was also evidence of overt toxicity in mice treated with 100% crude MCHM, although the severity was less than pure MCHM. Dermal application of crude MCHM resulted in increased lymphocyte proliferation in the draining lymph node at concentrations ≥5%. The Stimulation Index (SI), a measure of sensitization, was significantly increased in mice treated with ≥20% crude MCHM, relative to the vehicle control group. These results indicate that crude MCHM has the potential to cause dermal sensitization at exposure concentrations that are non-irritating. The PAC Mixtures Assessment Program (PAC-MAP) provides the framework for assessing a breadth of individual polycyclic aromatic compounds (PACs), defined PAC mixtures, and complex PAC-containing environmental samples using an in vitro/short-term in vivo testing battery that includes a broad spectrum of endpoints. Select PACs have been associated with a wide range of toxicities (carcinogenicity, immunotoxicity, reproductive and developmental toxicity, neurotoxicity) and a complicated array of mechanisms of action. In particular, many PACs have been associated with suppression of humoral immune function and immunotoxicity has been identified as an informative parameter for estimating the carcinogenic potential of PACs. As part of the potential testing battery to predict mixture effects, we have examined the potential for individual PACs to modulate the antigen specific antibody response and affect bone marrow cytology. Dose response studies for the positive control Benzo(a)pyrene and the less potent PAC, Phenanthrene have been completed and draft reports received for both studies. Laboratory protocols for three additional compounds, pyrene, dibenzothiophene and acenaphthenequinone, have been approved and the in life studies are expected to be completed in Q1FY17. The in-life portion of an assessment of the potential immunotoxicity oral exposure to the groundwater contaminant sulfolane has been completed in adult mice and rats exposed throughout development and early adulthood. Screening studies to assess immune function following exposure to the drinking water contaminate sodium metavanadate have also been completed. Draft reports for these studies are expected in Q1FY17. Two sets of immunotoxicity studies, conducted in B6C3F1/N mice and HSD rats following 30-day inhalation exposures to multi walled carbon nanotubes have been completed and the in life work for a third study, with an exposure duration of 90 days, is ongoing.